There are many human diseases which result in the formation of cysts which contain either semi-solid or fluid material. The contents of a cyst sometimes drive from normally retained fluid (e.g. a sebaceous cyst can contain fluid from a blocked sebaceous gland) or from a parasitic infection. Benign cysts can occur in the ovary, spleen, lungs, kidney and liver, where they are often congenital. Some congenital cysts result from fetal malformations and developmental failure while others are directs results of a disease state.
The polycystic kidney diseases (PKD) are a group of disorders characterized by the presence of a large number of fluid-filled cysts throughout grossly enlarged kidneys (Gabow et al., Diseases of the Kidney, Schrier et al. eds., 1992). In humans, PKDs can be inherited in autosomal dominant (ADPKD) or autosomal recessive (ARPKD) forms. ADPKD is the most common, dominantly-inherited kidney disease in humans, occurring at a frequency of about 1 in 800. ARPKD occurs at a frequency of about 1 in 10,000. Clinically, PKD represents a major cause of end-stage renal disease. Microdissection, histochemical and immunologic studies show that cysts in ARPKD kidneys arise from focal dilations of medullary collecting ducts (McDonald, Semin. Nephrol., 11:632-642, 1991). Mutations in at least three different loci have been associated with ADPKD in humans, including PKD1 on chromosome 16, PKD2 on chromosome 4, and the not yet mapped PKD3 (Reeders et al., Nature, 317:542-544, 1985; Kimberling et al., Genomics, 18:467-472, 1993; Daoustet al., Genomics, 25:733-736,1995). The ARPKD mutation is found on human chromosome 6 (Zerres et al., Nature Genet., 7:429-432, 1994). The molecular mechanisms leading to cyst enlargement and progressive loss of renal function in PKDs are not completely understood. Besides dialysis and transplantation, which are palliative, there are no preventive or curative treatment for PKDs.
In 1977, it was reported that a recessive congenital polycystic kidney (cpk) disease arose spontaneously in C57BL/6J mice (Preminger et al., J. Urol., 127:556-560, 1982). The cpk mutation has been mapped to mouse chromosome 12 (Davisson et al., Genomics, 9:778-781, 1991). Kidney maldevelopment and progression of PKD in C57BL/6-cpk/cpk mice have been characterized in detail (Preminger, ibid.; Mandell et al., Am. J. Pathol., 113:112-114, 1983). Affected animals appear normal at birth and have microscopic dilations of their proximal renal tubules. These enlarged tubules develop into cysts. At 10-13 days of age, homozygous cpk/cpk animals may be recognized by protuberant abdomens resulting from greatly enlarged kidneys. After day 10-12, additional cysts develop rapidly from dilations of medullary collecting ducts. Consequently, the kidneys rapidly enlarge, reaching almost 2.0 g in kidney weight at day 24 compared to about 0.18 g for age-matched normal kidneys. Cystic expansion is accompanied by the apoptotic loss of non-cystic nephrons (Woo, New Engl. J. Med., 333:18-25, 1995). Concomitant with kidney enlargement, there is a gradual decrease in kidney function with blood urea nitrogen (BUN) reaching 120 mg/dL by 24 days of age. Polycystic mice become progressively lethargic and die by 28-35 days of age due to renal failure.
Hallmark features of cystic changes in human PKD epithelia such as cellular hyperplasia and abnormal basement membrane are observed in cpk cysts at both the light and electron microscopic level (Gattone et al., Am. J. Kidney Dis., 17:606-607, 1991). The accumulation of fluid in cysts indicates abnormal fluid transport in cpk cystic epithelia. The presence of altered expression of basement membrane (Taub et al., Kidney Int., 37:1090-1097, 1990; Ebihara et al., Lab. Invest., 58:262-269, 1988), altered growth-controlling gene expression (Horikoshi et al., Kidney Int., 39:57-62, 1991; Gattone et al., Dev. Biol., 138:225-230, 1990; Cowley et al., J. Am. Soc. Nephrol., 1:1048-1053, 1991), altered targeting of the normally basolaterally sodium-potassium ATPase and EGF receptor (Avner et al., Proc. natl. Acad. Sci. U.S.A., 89:7447-7451, 1992; Orellana et al., Kidney Int., 47:490-499, 1995), and expression of developmentally dedifferentiated phenotypes (Harding et al., Dev. Biol., 146:483-490, 1991) make the cpk mouse a useful animal for studying the diverse renal pathobiologies of PKD. The overall progression of PKD is very similar in the cpk mouse and in humans.
The microtubule-specific drug taxol significantly inhibits the progression of PKD and significantly prolongs the survival of polycystic cpk mice (Woo et al., Nature, 368:750-753, 1994; PCT W094/08041). Instead of dying of azotemia by four to five weeks of age, polycystic mice treated weekly with taxol can survive to more than six months of age. Taxol binds to microtubules and inhibits microtubule depolymerization. Accordingly, the microtubule cytoskeleton has been postulated to play a role in pathogenesis of PKD in the cpk mouse. In addition to its microtubule stabilizing effects, taxol specifically induces the expression of tumor necrosis factor-.alpha. (TNF-.alpha.) in macrophages and lymphocytes. The ability of taxol to induce production of TNF-.alpha. is not shared by other members of the taxane family.
TNF-.alpha. is a pleiotropic cytokine that mediates diverse cellular responses including cytotoxicity, cytostasis, proliferation, differentiation and the expression of specific genes (Beutler et al., Science, 264:667-668, 1994). TNF-.alpha. is cytotoxic for a wide variety of tumor cells, but only toxic to a few selected normal cell types (Carswell et al., Proc. Natl. Acad. Sci. U.S.A., 72:3666-3670, 1975; Tsujimoto et al., Proc. Natl. Acad. Sci. U.S.A., 82:7626-7630, 1985). Despite the presence of cell surface TNF-.alpha. receptors, the majority of normal mammalian cells are resistant to the cytotoxic effects of TNF-.alpha. (Tsujimoto et al., ibid.). In addition, TNF-.alpha. is protective against apoptotic cell death in several cell types (Wong et al., Science, 242:941-944, 1988; Mangan et al., J. Immunol., 146:1541-1546, 1991; Warner et al., Am. J. Physiol., 260:L296-L301, 1991).
Thus, there is a need for a therapeutic agent capable of treating cystic disease. The present invention satisfies this need.